tbuckley/cabot-search huggingface dataset:
Abstract 1736: Local treatment of lung cancer by inhaled monoclonal antibodies: A pre-feasibility screening approach for spray drying
Authors: Madeleine Landry, Amanda Pluntze, Kimberly Shepard
Journal: Cancer Research (2022)

Abstract Local treatment of asthma and COPD by inhaled therapies has been standard of care for decades. A similar approach for lung cancer treatment could bring many benefits to the patient, including ease of administration, non-invasiveness, and potential for reduced side effects. Spray drying is a versatile, scalable manufacturing technique used to engineer therapies for delivery to the lung by dry powder inhaler. It is applicable to nearly all classes of molecules, including RNA, small molecules and proteins. Spray dried inhalation powders eliminate the need for cold chain storage, and can improve product shelf life compared with liquid formulations, improving access for developing nations and rural populations. Recently, inhaled delivery for a VEGF inhibitor, bevacizumab, has shown in preclinical studies to reduce tumor burden in rats at 1/10th the dose of injected bevacizumab, when combined with chemotherapy. To enable the next generation of inhaled monoclonal antibody (mAb) therapies by spray drying, mAb structural integrity is key. Spray dried materials undergo thermal and shear stresses, which can damage delicate mAbs. Herein we identified a set of analytical tests to evaluate the upper limits of heat and shear mAbs can withstand during spray drying. We exposed five cancer-relevant, FDA-approved mAbs to varying heat and shear stress then characterized changes to primary (1°), secondary (2°), and tertiary (3°) structure and binding activity indicative of degradation. Using the following analytical techniques we detected graduations of degradation: capillary electrophoresis-isoelectric focusing (1°), Fourier transform infrared spectroscopy (2°), Raman spectroscopy (2°), size exclusion chromatography (3°), absorbance and fluorescence spectroscopy (3°), dynamic light scattering (3°), multi-cell differential scanning calorimetry (3°), SDS-PAGE (3°), and binding activity ELISAs. Using these techniques, we developed a materials-sparing protocol to first assess whether an antibody is a candidate for spray drying, and second, to identify ideal process conditions for mAb spraying drying success. This approach will help to accelerate the development of inhaled protein therapies for lung cancer and other lung diseases. Citation Format: Madeleine Landry, Amanda Pluntze, Kimberly Shepard. Local treatment of lung cancer by inhaled monoclonal antibodies: A pre-feasibility screening approach for spray drying [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1736.
Abstract LB029: Comprehensive structure-function evaluation of the SHOC2 holophosphatase reveals disease mechanisms and therapeutic opportunities
Authors: Jason Kwon, Behnoush Hajian, Yuemin Bian, Alvaro Amor, James Fuller, Cara Fraley, Laura Baker, Jonathan So, David Mayhew, Abbey Sykes, Nicole Persky, Xiaoping Yang, David Root, Charles Perry, Christopher Lemke, William Hahn, Andrew Aguirre
Journal: Cancer Research (2022)

Abstract Receptor tyrosine kinase (RTK)-RAS signaling through the downstream mitogen activated protein kinase (MAPK) cascade regulate cell proliferation and survival. The SHOC2 holophosphatase functions as a key regulator of RTK-RAS signaling by removing an inhibitory phosphorylation on RAF family proteins to potentiate MAPK signaling. SHOC2 forms a ternary complex with MRAS and PP1C, and human germline gain-of-function mutations of this complex result in congenital RASopathy syndromes. However, the structure and the assembly of this complex are poorly understood. Here, we use cryogenic electron microscopy (cryo-EM) to resolve the structure of the SHOC2-PP1C-MRAS holophosphatase to 2.9Å resolution. Furthermore, we define the biophysical principles of SHOC2 holoenzyme interactions, elucidate the assembly order of the complex, and systematically interrogate the functional consequences of nearly all possible missense variants of SHOC2 through deep mutational scanning. We demonstrate that SHOC2 binds PP1C and MRAS through a concave surface created by the leucine-rich repeat region and further engages PP1C through the N-terminal disordered region containing a degenerate RVxF motif. Initial complex formation is mediated by SHOC2-PP1C interactions and is stabilized by binding of GTP-loaded MRAS. These observations define how clinical mutants in Noonan-like syndrome and cancer stabilize interactions of complex members to enhance holophosphatase activity. Together, this integrative structure-function model comprehensively defines key binding interactions within the SHOC2 holophosphatase, informing therapeutic development. Citation Format: Jason Kwon, Behnoush Hajian, Yuemin Bian, Alvaro Amor, James Fuller, Cara Fraley, Laura Baker, Jonathan So, David Mayhew, Abbey Sykes, Nicole Persky, Xiaoping Yang, David Root, Charles Perry, Christopher Lemke, William Hahn, Andrew Aguirre. Comprehensive structure-function evaluation of the SHOC2 holophosphatase reveals disease mechanisms and therapeutic opportunities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB029.
Abstract 3853: Investigating PRL2/<i>PTP4A2</i> as a new target for glioblastoma treatment
Authors: Tiffanie Chouleur, Marie-Alix Derieppe, Wilfried Souleyreau, Michel L. Tremblay, Andreas Bikfalvi
Journal: Cancer Research (2022)

Abstract Glioblastoma (GBM) is the most aggressive primary brain tumor. The standard treatment consists in tumor resection followed by chemo- and radio- therapy. However, tumor recurrence still remains inevitable, and the average lifespan of patients is only 15 months. Over the past decades, targeted therapies such as anti-angiogenic therapy, were proposed but failed to improve overall survival. In this context, the identification of new therapeutic targets is fundamental to implement current treatments. Protein Tyrosine Phosphatases (PTPs) are known to be involved in oncogenesis in several types of cancer, including GBM. Oncogenic properties of PRL2 has been demonstrated in different tumors (e.g. leukemia, breast, lung and nasopharyngeal cancer), but no evidence of PRL2 involvement in GBM has been reported so far. The aim of this project is to understand the role of PRL2 in GBM development, in order to evaluate the potential of PRL2 inhibition as a new therapeutic strategy. Analysis of TCGA (The Cancer Genome Atlas) dataset revealed that PRL2 was a poor prognostic factor in gliomas, and its expression correlated GBM aggressiveness. PTP4A2 expression also correlated with expression of genes involved in immune responses, reactive oxygen species, actin cytoskeleton and trafficking. Thus, we oriented our work towards these directions. To study PRL2 effects both in brain tumor cells and microenvironment, we used spheroids of patient-derived GBM cells, in which PTP4A2 expression was modulated. In vitro assays showed that migration, invasion and adhesion abilities were increased in PTP4A2-KO cells but cell proliferation was not affected. Next, in orthotopic xenografts experiments, PRL2 over-expression promoted tumor growth and reduced mouse survival rate. In addition, to overcome PRLs functional compensation and to use a clinically relevant strategy, we targeted all PRLs (PRL1, 2 and 3) activity with an inhibitory compound. Inhibiting all PRLs drastically reduced viability of GBM cells. Our project aims at discovering how PRL2 is involved in the progression and tumor microenvironment of GBM. Our results indicate that PRL2 promotes GBM growth in response to microenvironmental pressure and its inhibition improves mouse outcomes. However, the precise mechanisms of this regulation are still under investigation. Targeting PRLs and particularly PRL2 open avenue for therapeutic strategy in GBM treatment. Citation Format: Tiffanie Chouleur, Marie-Alix Derieppe, Wilfried Souleyreau, Michel L. Tremblay, Andreas Bikfalvi. Investigating PRL2/PTP4A2 as a new target for glioblastoma treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3853.
Abstract 2255: Alu retroelement copy number alterations and non-Hodgkin lymphoma
Authors: Wei Hu
Journal: Cancer Research (2022)

Abstract Background: Alu retrotransposons are repetitive DNA elements that make up nearly 10% of the human genome and reflect genomic instability. Genomic instability plays an important role in the pathogenesis of non-Hodgkin lymphoma (NHL). However, the relationship between Alu retrotransposons and future risk of NHL is unclear. Methods: We conducted a nested case-control study of NHL risk and Alu retroelement copy number within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) study, a prospective cohort with prediagnostic blood samples from 29,133 male Finnish smokers. We measured Alu copy number in 107 incident NHL cases and 1:1 matched controls (± 5 years age). DNA samples extracted from blood were assayed in triplicate using a monochrome multiplex quantitative polymerase chain reaction. We used the albumin gene for the single copy gene to control for genome content in samples. The odds ratios (OR) and 95% confidence intervals (CI) for all NHL were estimated using conditional logistic regression models, adjusting for age at randomization, number of cigarettes smoked per day and smoking duration. Polytomous logistic regression models were fit to compute ORs with Alu copy number for NHL subtypes. To determine if the association might be driven in part by elevated Alu copy number among undiagnosed cases at the time of blood sample collection, we excluded cases diagnosed within the first two years of follow-up. Results: Higher Alu copy number (using the median as the cut-point) was associated with an increased risk of NHL, both overall [OR, 95% CI=3.80 (1.76-8.17)] as well as for the diffuse large B-cell lymphoma [OR, 95% CI=4.83 (1.50-15.55)] and chronic lymphocytic leukemia/small lymphocytic lymphoma (SLL) [OR, 95% CI=2.66 (1.10-6.40)] subtypes. These associations were similar after excluding individuals diagnosed with NHL within two years after blood draw. Conclusions: These findings, which require replication, suggest that higher Alu copy number in prediagnostic leukocytes may play a role in the pathogenesis of NHL. Citation Format: Wei Hu. Alu retroelement copy number alterations and non-Hodgkin lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2255.
Rammya Mathew: Celebrating the quality and calibre of GPs
Authors: Rammya Mathew
Journal: BMJ (2022)

<h3>Abstract</h3> <h3>Objective</h3> Emerging SARS-COV-2 variants are spurring the development of adapted vaccines as public health authorities plan for the fall vaccination strategy. We aimed to estimate the number of infections and hospitalizations prevented by three potential booster strategies in those ≥18 years of age in the United States: Boosting with Moderna’s licensed first generation monovalent vaccine mRNA-1273 (ancestral strain) starting in September 2022, boosting with Moderna’s candidate bivalent vaccine mRNA-1273.214 (ancestral + BA.1 variant of concern [VOC]) starting in September 2022, or boosting with Moderna’s updated candidate bivalent vaccine mRNA-1273.222 (ancestral + BA.4/5 VOC) starting 2 months later in November 2022 due to longer development timeline. <h3>Methods</h3> An age-stratified, transmission dynamic, Susceptible-Exposed-Infection-Recovered (SEIR) model, adapted from previous literature, was used to estimate the number of infections over time; the model contains compartments defined by both SEIR status and vaccination status. A decision tree was subsequently used to estimate the clinical consequences of those infections. Calibration was performed so the model tracks the actual course of the pandemic up to the present time. <h3>Results</h3> Vaccinating with mRNA-1273(Sept), mRNA-1273.214(Sept), and mRNA-1273.222(Nov) is predicted to reduce infections by 34%, 40%, and 18%, respectively, over a 6-month time horizon (September-February) compared to no booster. Similarly, boosting in September prevents substantially more hospitalizations than starting to boost in November with a more effective vaccine (42%, 48%, and 25% for mRNA-1273, mRNA-1273.214, and mRNA-1273.222, respectively, at 6 months compared to no booster). Sensitivity analyses around transmissibility, vaccine coverage, masking, and waning of natural and vaccine-induced immunity changed the magnitude of cases prevented but boosting with mRNA-1273.214 in September consistently prevented more cases of infection and hospitalization than the other two strategies. <h3>Limitations and Conclusions</h3> With the emergence of new variants, key characteristics of the virus that affect estimates of spread and clinical impact also evolve, making estimation of these parameters difficult, especially in heterogeneous populations. Our analysis demonstrated that vaccinating with the bivalent mRNA-1273.214 booster was more effective over a 6-month period in preventing infections and hospitalizations with a BA.4/5 subvariant than the tailored vaccine, simply because it could be deployed 2 months earlier. We conclude that there is no advantage to delay boosting until a BA.4/5 vaccine is available; earlier boosting with mRNA-1273.214 will prevent the most infections and hospitalizations.
Abstract 629: Benefit of using a spectral flow analyzer for the analysis of immune cell populations in tumors
Authors: Philipp Metzger, Muriel Malaisé, Cynthia Obodozie, Holger Weber
Journal: Cancer Research (2022)

Abstract Flow cytometry is a widely applied approach for exploratory immune profiling and enables the identification of individual cells in a cell population, such as a tumor cell suspension, by staining cell markers with antibodies conjugated with a fluorophore. The markers allow for the differentiation of a large variety of immune cell populations, their change in frequency, and activation status upon treatment. Conventional flow cytometers, which use bandpass filters and need conventional compensation matrices, are limited by the number of parameters that can be simultaneously analyzed, restricting their utility. Spectral analysis technology promises a greater flexibility for panel design, a higher number of analyzed parameters, and more accurate visualization of results. Our standard all-in-one flow cytometry panel uses all possible fluorescent detectors of the flow analyzer BD Fortessa, which permits the differentiation of the main immune cell populations in the tumor, such as T cells (CD4+, CD8+, Treg), B and NK cells, macrophages (M1/M2), MDSCs (granulocytic and monocytic), and dendritic cells. However, in addition to immune cell frequency, it would also be interesting to investigate cell surface activation and memory markers like PD-1, CD40, CD44, or CD62L or intracellular activation markers like IFN-gamma, perforin, granzyme B, or Ki67. The 32-channel spectral flow analyzer SP6800 ZE from Sony allows the combination of both. Flow cytometry data of different tumor samples will be presented, as well as the comparison of the results and resolution of both flow analyzer systems. Auto-fluorescence of cells, which causes fluorescent signal contamination of other fluorescent markers in the conventional flow cytometer, can be subtracted using spectral technology to see the true fluorescent population, thereby allowing dim signal detection in rare populations. A comprehensive overview will be given regarding the pros and cons of the spectral analyzer system and difficulties switching from the one system to the other. Citation Format: Philipp Metzger, Muriel Malaisé, Cynthia Obodozie, Holger Weber. Benefit of using a spectral flow analyzer for the analysis of immune cell populations in tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 629.
Abstract 153: An unbiased <i>in vitro</i> screen for activating ERBB4 mutations
Authors: Deepankar Chakroborty, Veera K. Ojala, Anna M. Knittle, Kari J. Kurppa, Klaus Elenius
Journal: Cancer Research (2022)

Abstract Introduction: Cancer tissues harbor thousands of mutations, and a given oncogene may be mutated at hundreds of sites across different samples. The discovery of most of the currently known driver mutations has been facilitated by their accumulation in mutation hotspots within their respective genes. However, a vast majority of mutations in cancer tissues are rare and their functional significance remains unknown. Several lines of in vitro and clinical evidence also indicate that there is a significant number of, as yet unidentified, activating driver mutations which could serve as predictive markers in oncology. Here, we performed an unbiased functional screen to identify potential activating mutations of ERBB4, a frequently mutated member of the epidermal growth factor receptor family. Method: To identify functional driver mutations of ERBB4, the previously published pipeline, in vitro screen for activating mutations (iSCREAM) [1], was utilized. iSCREAM is a functional genetics screen based on the expression of random cDNA variants and the ability of driver mutations to promote cellular growth in vitro. The expression library encoding randomly mutated ERBB4 variants was retrovirally introduced into murine lymphoid Ba/F3 cells, that normally require interleukin-3 (IL-3) for survival but can exploit ectopic expression of activated variants of oncogenic kinases to compensate for the deficiency of exogenous IL-3. When expressed under an appropriate promoter, the wild-type ERBB4 receptor failed to promote IL-3-independent survival in the presence of the neuregulin-1 ligand, while the cells expressing activating mutations readily proliferated. The identity and frequency of the activating ERBB4 mutations were subsequently determined from the proliferating cell pool using targeted next-generation sequencing. Results: Ten candidate activating mutations were identified out of the over 7000 random ERBB4 missense or nonsense mutations present in the original library. The candidate activating mutations were individually characterized using functional assays both in vitro and in vivo, as well as by structural analyses. The activating mutation were sensitive to clinically used pan-ERBB tyrosine kinase inhibitors afatinib, dacomitinib and neratinib. Conclusions: A subset of ERBB4 missense mutations are activating and sensitive to tyrosine kinase inhibitor drugs. Citation Format: Deepankar Chakroborty, Veera K. Ojala, Anna M. Knittle, Kari J. Kurppa, Klaus Elenius. An unbiased in vitro screen for activating ERBB4 mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 153.
Abstract 733: Adolescent dietary patterns in relation to later prostate cancer risk and mortality in the NIH-AARP diet and health study
Authors: Tuo Lan, Yikyung Park, Graham A. Colditz, Jingxia Liu, Molin Wang, Kana Wu, Edward Giovannucci, Siobhan Sutcliffe
Journal: Cancer Research (2022)

Abstract Background: Although adolescent diet has been proposed to contribute to prostate cancer (PCa) development, no studies have investigated the relation between adolescent dietary patterns and PCa risk or mortality. Method: Using data from the NIH-AARP Diet and Health Study, we performed factor analysis to identify dietary patterns at ages 12-13 years. We further used Cox proportional hazards regression to examine hazard ratios (HRs) and 95% confidence intervals (CIs) of total, non-advanced, advanced, and fatal PCa. Results: During 1,878,681 person-years of follow-up, 17,861 men were diagnosed with PCa, including 15,499 non-advanced, 2,362 advanced, and 832 fatal cancers. Three adolescent dietary patterns were identified: a Western modern pattern characterized by greater intake of sweets, processed meat, beef, cheese, and pizza; a plant-based pattern characterized by greater intake of vegetables, fruits, and dark bread; and a Western traditional pattern characterized by greater intake of gravy, bacon, and chicken, eggs, potatoes, green beans, legumes, and white bread. Although not entirely consistent across analyses, a higher adolescent plant-based pattern score was associated with reduced risks of total PCa (fully-adjusted HRQ5vs.Q1=0.93, 95% CI: 0.89-0.98, p-trend=0.003) and non-advanced PCa (HR=0.91, 95% CI: 0.87-0.96, p-trend&amp;lt;0.001), whereas no associations were observed for Western modern or Western traditional patterns. Conclusions: In the first study, to our knowledge, to investigate adolescent dietary patterns and PCa risk, we found some evidence to support a protective role for a plant-based diet during adolescence on PCa risk. Our findings may inform the development of new, primary prevention strategies for PCa. Citation Format: Tuo Lan, Yikyung Park, Graham A. Colditz, Jingxia Liu, Molin Wang, Kana Wu, Edward Giovannucci, Siobhan Sutcliffe. Adolescent dietary patterns in relation to later prostate cancer risk and mortality in the NIH-AARP diet and health study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 733.